Genetic support for FDA drug approvals 2023
Last update: 09, September, 2024
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Introduction
What is the genetic support for the 55 drugs that were approved by the FDA this year (Mullard 2024)? To answer this question requires accessing all current knowledge regarding the association of the drug target to the disease and data analytics capabilities that are provided in platforms like DISGENET (Piñero et al. 2019).
Data
Preprocessing
We will remove from the analysis 4 drugs that target proteins from other organisms (Table 2). Note that two drugs, Defencath and Paxlovid, are combinations targeting both human and non-human organisms and will be included in the analysis using the human target.
| Drug_brand_name | Properties | Indication |
|---|---|---|
| Lotilaner (Xdemvy) | Ectoparasiticide | Demodex blepharitis |
| Nirsevimab (Beyfortus) | RSV F protein-targeted mAb | RSV lower respiratory tract disease |
| Rezafungin (Rezzayo) | Echinocandin antifungal | Candidemia and invasive candidiasis |
| Sulbactam, durlobactam (Xacduro) | β-lactam antibacterial plus a β-lactamase inhibitor | Hospital-acquired and ventilator-associated bacterial pneumonia caused by susceptible ABC |
… and 3 drugs that do not target a gene or protein (Table 3).
| Drug_brand_name | Properties | Indication |
|---|---|---|
| Birch triterpenes (Filsuvez) | Mechanism unknown | Epidermolysis bullosa |
| Pegunigalsidase alfa (Elfabrio) | PEGylated recombinant α-galactosidase Α | Fabry disease |
| Perfluorohexyloctane (Miebo) | Semifluorinated alkane | Dry eye disease |
Converting indications to UMLS identifiers
The remaining 48 drugs are indicated for 46 conditions. We mapped 48 indications to an exact Unified Medical Language System (UMLS) Concept Unique Identifiers (CUI), corresponding to 64 CUIs (Table 4). Using UMLS CUIs allowed more exact mappings of the indications for the drugs, due to the richer and more granular descriptions of phenotypes provided by the UMLS.
Indications with no direct mappings to UMLS were manually assign to similar terms (Table 5).
| Indication | diseaseid | disease_name | |
|---|---|---|---|
| 1 | AChR- or MuSK-antibody-positive gMG | C0751339 | Myasthenia Gravis, Generalized |
| 2 | AChR-antibody positive gMG | C0751339 | Myasthenia Gravis, Generalized |
| 3 | Anaemia caused by CKD for adults on dialysis | C0002871; C1561643 | Anemia; Chronic Kidney Diseases |
| 4 | Geographic atrophy secondary to AMD | C0242383; C1536085 | Age related macular degeneration; Geographic Atrophy |
| 5 | hATTR with polyneuropathy | C0152025 | Polyneuropathy |
| 6 | Non-CNS manifestations of α-mannosidosis | C0024748 | alpha-Mannosidosis |
| 7 | Proteinuria in primary IgA nephropathy | C0033687; C3161650 | Proteinuria; Primary immunoglobulin A nephropathy (disorder) |
| 8 | RSV lower respiratory tract disease | C0035235; C0149725 | Respiratory Syncytial Virus Infections; Lower respiratory tract infection |
| 9 | SOD1 amyotrophic lateral sclerosis | C0002736 | Amyotrophic Lateral Sclerosis |
Finally, one indication could not be mapped to any concept: (Haematopoietic stem cell mobilization for autologous transplantation in multiple myeloma).
Drug-target information
We used the indications from ChEMBL to find the targets for the FDA approvals (Table 7). All 48 drugs were found to be associated to at least one human target, and the total number of targets is 101
Results
We will use the DISGENET API to retrieve the genes associated to the indications. To perform this operation, you will need to register, to get an API key.
Exact mappings
Using DISGENET information, we find that 33 drugs have at least a gene associated to their indication ( 31) in DISGENET, thus 60 percent of the drugs are supported by genetic info, with exact mappings (counting only the ones that have a human target, thus 55 ).
Figure 1 shows the top scoring gene associated to the pair drug-indication.
Similar mappings
11 drugs where found to have at least a gene associated to their indication ( 11) in DISGENET using the similarity mapping, thus 80 percent of the drugs are supported by genetic info, with exact mappings or similar, out of the total new drugs 55.
Drugs with genetic support for the indication, or a disease similar to the indication
If we consider the drugs that target human proteins, the percent raises to 91.7.
Drug without genetic suppport
Drugs that do not have a genetic support are shown in the table below
| Indication | Drug_brand_name | Symbol | |
|---|---|---|---|
| 1 | Activated PI3Kδ syndrome | Leniolisib (Joenja) | PIK3CD |
| 2 | Haematopoietic stem cell mobilization for autologous transplantation in multiple myeloma | Motixafortide (Aphexda) | CXCR4 |
| 3 | Desmoid tumours | Nirogacestat (Ogsiveo) | APH1A; APH1B; NCSTN; PSEN1; PSEN2; PSENEN |
| 4 | CHAPLE disease | Pozelimab (Veopoz) | C5 |
Conclusion
In summary, this analysis shows that DISGENET provides genetic support for 91.7% of the drugs approved during 2023 by the FDA. Thus, DISGENET is a key resource for drug R&D to provide actionable information on potential targets for a wide range of indications. In addition, it illustrates the potential of DISGENET as a resource for information on disease biomarkers, as it also contains the evidence that relates the association of the biomarkers with their indications for the two imaging agents approved by the FDA.